ORGANIC LETTERS
The Formal [4 þ 3] Cycloaddition between Donor-Acceptor Cyclobutanes and Nitrones
2011 Vol. 13, No. 6 1528–1531
Andrew C. Stevens, Cory Palmer, and Brian L. Pagenkopf* Department of Chemistry, The University of Western Ontario, 1151 Richmond Street, London, Ontario, N6A 5B7, Canada
[email protected] Received January 24, 2011
ABSTRACT
The formal [4 þ 3] cycloaddition of 2-alkoxy-1,1-dicarboxylate activated donor-acceptor cyclobutanes with nitrones is disclosed. The reaction forms structurally unique oxazepines in moderate to high yield with a wide scope of nitrones. In most cases either a diastereomeric mixture or a single diastereomer may be formed, depending on the reaction conditions.
Cycloaddition chemistry persists as one of the premiere methods for the rapid formation of highly complex molecular scaffolds.1 New dipolar cycloadditions continue to be developed to address the need for tailored reactivity and the synthesis of unique or intriguing structural motifs.2 Nitrones, which are versatile 1,3-dipolarophiles, have been shown to undergo highly enantio- and regioselective [3 þ 2] cycloadditions with olefins to form functionalized oxazolines.3 Additionally, reactions of nitrones with (1) For reviews see: (a) Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products; Padwa, A., Pearson, W. H., Eds.; John Wiley & Sons, Inc.: New York, 2002. (b) Stanley, L. M.; Sibi, M. P. Chem. Rev. 2008, 108, 2887–2902. (2) For recent examples see: (a) Sumiya, T.; Ishigami, K.; Wantanabe, H. Angew. Chem., Int. Ed. 2010, 49, 5527–5528. (b) Creech, G. S.; Kwon, O. J. Am. Chem. Soc. 2010, 132, 8876–8877. (c) Repka, L. M.; Ni, J.; Reisman, S. E. J. Am. Chem. Soc. 2010, 132, 14418–14420. (d) Spiteri, C.; Kelling, S.; Moses, J. E. Org. Lett. 2010, 12, 3368–3371. (e) Gryko, D. T.; Rogacki, M. K.; Klajn, J.; Gazezowski, M.; Stepie n, K.; Cyra nski, M. K. Org. Lett. 2010, 12, 2020–2023. (3) For reviews see: (a) Tufariello, J. J. Acc. Chem. Res. 1979, 12, 396– 403. (b) Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98, 863–909. (c) Denmark, S. E.; Cottell, J. J. In Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products; Padwa, A., Pearson, W. H., Eds.; John Wiley & Sons: New York, 2003. (4) (a) Kinugasa, M.; Hashimoto, S. J. Chem. Soc., Chem. Commun. 1972, 466–467. (b) Lo, M. M.-C.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 4572–4573. (5) Zhang, X.; Hsung, R. P.; Li, H.; Zhang, Y.; Johnson, W. L.; Figueroa, R. Org. Lett. 2008, 10, 3477–3479. (6) Shindo, M.; Itoh, K.; Tsuchiya, C.; Shishido, K. Org. Lett. 2002, 4, 3119–3121. 10.1021/ol200220d r 2011 American Chemical Society Published on Web 02/22/2011
alkynes, ynamides, or ynolates have been used to prepare β-lactams,4 R-amino-β-lactams,5 or 5-isoxazolidinones,6 respectively. However, it was the seminal reports of Kerr and co-workers that demonstrated highly strained donor-acceptor (DA) cyclopropanes could engage in nitrone cycloadditions.7 While DA cyclopropanes have been extensively studied in cycloaddition chemistry,8 only recently have DA cyclobutanes, which share a similar degree of bond strain,9 been explored for related modes of reactivity. To date, only a handful of dipolarophiles have been shown to undergo reactions with cyclobutanes, including aldehydes,10 (7) (a) Young, I. S.; Kerr, M. A. Angew. Chem., Int. Ed. 2003, 42, 3023–3026. (b) Young, I. S.; Kerr, M. A. Org. Lett. 2004, 6, 139–141. (c) Ganton, M. D.; Kerr, M. A. J. Org. Chem. 2004, 69, 8554–8557. (8) For reviews see: (a) Reissig, H.-U. Top. Curr. Chem. 1988, 144, 73–135. (b) Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003, 103, 1151– 1196. (c) Yu, M.; Pagenkopf, B. L. Tetrahedron 2005, 61, 321–347. (d) Carson, C. A.; Kerr, M. A. Chem. Soc. Rev. 2009, 38, 3051–3060. (e) De Simone, F.; Waser, J. Synthesis 2009, 20, 3353–3374. (9) Wiberg, K. B. The Chemistry of Cyclobutanes, Part I; Rappoport, Z., Liebman, J. F., Eds.; John Wiley & Sons Ltd: Chichester, England, 2005; pp 4-5. (10) (a) Shimada, S.; Saigo, K.; Nakamura, H.; Hasegawa, M. Chem. Lett. 1991, 20, 1149–1152. (b) Matsuo, J.-I.; Sasaki, S.; Tanaka, H.; Ishibashi, H. J. Am. Chem. Soc. 2008, 130, 11600–11601. (c) Parsons, A. T.; Johnson, J. S. J. Am. Chem. Soc. 2009, 131, 14202–14203. (d) Allart, E. A.; Christie, S. D. R.; Pritchard, G. J.; Elsegood, M. R. Chem. Commun. 2009, 47, 7339–7341. (e) Moustafa, M. M. A. R.; Stevens, A. C.; Machin, B. P.; Pagenkopf, B. L. Org. Lett. 2010, 12, 4736–4738. (f) Negishi, S.; Ishibashi, H.; Matsuo, J.-I. Org. Lett. 2010, 12, 4984–4987.
ketones,10a,b imines,11 silylenolethers,12 and allylsilanes.13 In this letter we disclose the first example of a formal [4 þ 3] cycloaddition between alkoxy-substituted DA cyclobutanes and nitrones for the generation of structurally unique oxazepines.14 This intriguing structural motif, though not naturally occurring, has been shown to be relevant as analogues of eudistomin natural products that display antiviral15 and antiproliferative16 activity. Yb(OTf)3 has previously been shown to be an effective catalyst for the reaction between nitrones and cyclopropanes activated by geminal diesters,7,17 as well as in recent work for cyclobutane cycloadditions,10e,11b and thus was selected initially for optimization studies (Table 1). Much to our delight, upon addition of cyclobutane 2 to a solution of nitrone 1 and 10 mol % of Yb(OTf)3 in dichloromethane, the anticipated cycloadduct 3a was formed as a single diastereomer in 60% isolated yield (Table 1, entry 1).18 Control tests demonstrated that a metal catalyst was not required for the reaction to occur; however, extended reaction times were necessary and a mixture of two apparently nonequilibrating diastereomers resulted (entry 2). A modest increase in yield was observed when the nitrone, rather than the cyclobutane, was used as the limiting reagent (compare entries 1 and 3). When the catalytic loading was decreased from 10 mol % to 5 mol % a mixture of two diastereomers was found if the reaction was stopped after 10 min (entry 4), and the diastereomeric ratio reversed when the reaction was conducted at 0 °C (entry 5). In all cases, increasing the reaction time or catalyst loading led ultimately to the single diastereomer 3a (entry 6) and, as expected, exposure of 3b to Yb(OTf)3 resulted in isomerization to 3a. To date conditions have not been identified that allow for exclusive formation of the trans diastereomer 3b despite exploring various temperatures, catalysts, and solvents. Interestingly, decreasing the catalytic loading of Yb(OTf)3 to 1 mol % resulted in the formation of three diastereomers.19 The breadth of the cycloaddition reaction was then examined, and separate experiments were conducted to obtain both diastereomeric mixtures and a single diastereomer. The electronics of the nitrone were first investigated, and a significant impact on the length of time required for single diastereomer formation was found (Table 2). While electron(11) (a) Matsuo, J.-I.; Okado, R.; Ishibashim, H. Org. Lett. 2010, 12, 3266–3268. (b) Moustafa, M. M. A. R.; Pagenkopf, B. L. Org. Lett. 2010, 12, 4732–4735. (12) Matsuo, J.-I.; Negishi, S.; Ishibashi, H. Tetrahedron Lett. 2009, 50, 5831–5833. (13) Matsuo, J.-I.; Sasaki, S.; Hoshikawa, T.; Ishibashi, H. Org. Lett. 2009, 11, 3822–3825. (14) Oxazepines have been made by the reaction of 1-(1-alkynyl) cyclopropyl ketones with nitrones: Zhang, Y.; Liu, F.; Zhang, J. Chem.Eur. J. 2010, 16, 6146–6150. (15) Kurihara, T.; Sakamoto, Y.; Kimura, T.; Ohishi, H.; Harusawa, S.; Yoneda, R.; Suzutani, T.; Azuma, M. Chem. Pharm. Bull. 1996, 44, 900–908. (16) van Maarseveen, J. H.; Scheeren, H. W.; De Clercq, E.; Balzarini, J.; Kruse, C. G. Bioorg. Med. Chem. 1997, 5, 955–970. (17) (a) Hu, B.; Zhu, J.; Xing, S.; Fang, J.; Du, D.; Wang, Z. Chem.Eur. J. 2009, 15, 324–327. (b) Wu, L.; Shi, M. Chem.-Eur. J. 2010, 16, 1149–1152. (18) 4 A˚ molecular sieves were needed to prevent hydrolysis of the nitrone. (19) A mixture of three diastereomers was formed, cis:trans:third 1.0:1.4:1.4, 95% yield. Org. Lett., Vol. 13, No. 6, 2011
Table 1. Optimization of the [4 þ 3] Cycloaddition of DA Cyclobutanes and Nitrones
entry
1 (equiv)
2 (equiv)
Yb(OTf)3 (mol %)
time (min)
3a:3b
yield (%)
1 2 3 4 5 6
1.5 1.5 1.0 1.0 1.0 1.0
1.0 1.0 1.2 1.2 1.2 1.2
10 0 10 5 5 5
10 60 10 10 10 60
1.0:0.0 1.3:1.0 1.0:0.0 1.7:1.0 1.0:2.2 1.0:0.0
60 87a 81 78 91b 76
Reaction conducted in the presence of 4 A˚ molecular sieves. In the absence of both molecular sieves and Lewis acids, no reaction occurs. b Reaction conducted at 0 °C. a
Table 2. Effect of C-Substitution on the Cyclobutane/Nitrone Cycloaddition
diastereomeric mixturea
entry
nitrone
1 2 3 4 5
Ar = C6H5 Ar = p-C6H4OCH3 Ar = p-C6H4Cl Ar = p-C6H4CN Ar = p-C6H4NO2
single cis dr diastereomerb yield (%) (trans:cis 3rd) yield (%) 91 88 82 95 90
69:31 63:37 71:29 57:15:27 63:11:26
76c 74c 73c 76d 73d
a Conditions: 0 °C, 15 min. b Conditions: 22 °C, reaction allowed to proceed until only a single product was observable by TLC. c Reactions required less than 1 h to form single diastereomers. d Reactions required 24 h to form single diastereomers.
rich nitrones required less than an hour for the reaction to yield a single diastereomer (entries 1-3), electron-deficient nitrones required extended reaction times (up to 24 h) to allow for full equilibration (entries 4 and 5). Additionally, with electron-deficient nitrones (entries 4 and 5) the 1529
formation of an apparent third inseparable/transient diastereomer (not isolated) was observed with short reaction times. The yields were found to be consistent regardless of the
Figure 1. X-ray structure of the cis and trans diastereomers of Table 2, entry 3.
electronic nature of the nitrone, though the extended times required for equilibrating the diastereomeric mixtures resulted in lower yields due to competing background decomposition. The stereochemistry of the cis and trans diastereomers was assigned according to NOE interactions. In the case of entry 3, the stereochemistry of both diastereomers was unambiguously confirmed by single-crystal X-ray analysis (Figure 1). Next, the effect of N-substitution on the nitrone was examined (Table 3). Nitrones bearing an electron-deficient N-aryl group were found to be viable reaction partners (entries 2 and 3). Electron-rich N-PMP nitrones underwent the cycloaddition to afford PMP-protected oxazepines (entries 4-6). It was also discovered that N-benzyl nitrone reacts to provide a single diastereomer (entry 7). Having found the reaction to be compatible with a variety of nitrones, additional functionalities of the Csubstituents were explored (Table 4). It was discovered that heteroaromatic nitrone substituents worked well in the cycloaddition (entries 1 and 2). Surprisingly, when napthyl- or cinnamyl- substituted nitrones were subjected
Table 4. Exploration of Nitrone Functionality Tolerance in the Cycloaddition
Table 3. Effect of N-Substitdution of the Cycloaddition of DA Cyclobutanes and Nitrones
diastereomeric mixturea
entry
nitrone
1 R = C6H5 Ar = C6H5 2 R = p-C6H4CO2Me Ar = C6H5 3 R = p-C6H4CO2Me Ar = p-C6H4NO2 4 R = p-C6H4OMe Ar = C6H5 5 R = p-C6H4OMe Ar = p-C6H4CN 6 R = p-C6H4OMe Ar = p-C6H4OMe 7 R = Bn Ar = C6H5
yield dr (cis: single cis (%) trans:3rd) diastereomerb yield (%) 91
31:69
76
68
16:40:44
52c
74
7:58:35
68
69
34:66
43
66
32:68
55
70
56:44
54 60
a Conditions: 0 °C, 15 min. b Conditions: 22 °C, reaction allowed to proceed until only a single product was observable by TLC. c Incomplete conversion, 72:28 cis:trans after 24 h and 10 mol % Yb(OTf)3.
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Conditions: 0 °C, 15 min. b Conditions: 22 °C, reaction allowed to proceed until only a single product was observable by TLC. a
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Scheme 1. Alternative Cyclobutanes in the Cycloaddition
to the reaction conditions only single diastereomers were observed rather than diastereomeric mixtures, similar to the results obtained with N-alkyl substitution (Table 4, entries 3 and 4 vs Table 3, entry 7). It was found that Csubstitution was not necessary for the reaction as a Cunsubstituted benzyl nitrone underwent the reaction to form exclusively the cis adduct (entry 5). Lastly, two additional cyclobutanes were subjected to the reaction conditions with several nitrones. A pyranfused cyclobutane was found to react with nitrones to
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produce diastereomeric cycloadducts (Scheme 1, entries 1-3). An ethoxy-substituted cyclobutane also successfully formed the oxazepines in good yield (entries 4 and 5). The highly crystalline material of entry 5 allowed for the collection of single-crystal X-ray data which permitted unambiguous assignment of the two diastereomers formed during the reaction. In conclusion, we have reported the formal [4 þ 3] cycloaddition between alkoxy-activated DA cyclobutanes and nitrones to afford structurally unique, 2,3,4,6,7-substituted oxazepines. The reaction, in most cases, initially affords a diastereomeric mixture, which equilibrates to a single diastereomer. To date, all nitrones examined successfully participated in the cycloaddition reaction. Efforts are currently underway to develop asymmetric variants of this methodology, identify new dipolarophile partners for the reaction with DA cyclobutanes, and exploit this new cycloaddition for the synthesis of natural products. Acknowledgment. We thank the University of Western Ontario and the National Sciences and Engineering Research Council of Canada (NSERC) for financial support. We thank Mahmoud Moustafa (UWO) for helpful discussions. We also thank Dr. Doug Hairsine (UWO) for high-resolution mass spectrometry and Dr. Guerman Popov (UWO) for X-ray crystallographic analysis. Supporting Information Available. Detailed experimental procedures, copies of NMR spectra, and X-ray crystal data. This material is available free of charge via the Internet at http://pubs.acs.org.
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